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Intratumoral IL-12 and TNF-–Loaded Microspheres Lead To Regression of Breast Cancer and Systemic Antitumor Immunity

From the Division of Surgical Oncology (MSS, JS, W-JC, AEC) and Department of Pathology (LS), University of Michigan, Ann Arbor, Michigan; SUNY at Buffalo (NKE), Buffalo, New York; and Brown University (EM, NB), Providence, Rhode Island.

Correspondence: Address correspondence and reprint requests to: Michael S. Sabel, MD, Asst. Professor of Surgery, Division of Surgical Oncology, University of Michigan Comprehensive Cancer Center, 3304 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109–0932; Fax: 734-647-9647; E-mail: msabel{at}umich.edu

Background: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor (TNF-), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response.

Methods: BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon (IFN) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis.

Results: Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF- leading to increased infiltration by polymorphonuclear cells and CD8⁺ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN- production, was highest with IL-12 and TNF-. This treatment resulted in resistance to tumor rechallenge.

Conclusions: A single intratumoral injection of IL-12 and TNF-–loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8⁺ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.

Key Words: Breast cancer • IL-12 • Immunotherapy • Microspheres • TNF-

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